epz-6438 and Colorectal-Neoplasms

Although the survival rate of patients with cancer have increased due to the use of current chemotherapeutic agents, adverse effects of cancer therapy remain a concern. The reversal of drug resistance, reduction in harmful side effects and accelerated increase in efficiency have often been addressed in the development of combination therapeutics. Tazemetostat (EPZ-6438), a histone methyltransferase EZH2 selective inhibitor, was approved by the FDA for the treatment of advanced epithelioid sarcoma. However, the effect of tazemetostat on colorectal cancer (CRC) and 5-FU sensitivity remains unclear. In this study, the enhancement of tazemetostat on 5-FU sensitivity was examined in CRC cells. Our findings demonstrated that tazemetostat combined with 5-FU exhibits synergistic antitumor function in vitro and in vivo in CRC cells. In addition, tazemetostat promotes PUMA induction through the ROS/ER stress/CHOP axis. PUMA depletion attenuates the antitumor effect of the combination therapy. Therefore, tazemetostat may be a novel treatment to improve the sensitivity of tumors to 5-FU in CRC therapy. In conclusion, the combination of 5-FU and tazemetostat shows high therapeutic possibility with reduced unfavorable effects.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Benzamides; Biphenyl Compounds; Cell Line, Tumor; Colorectal Neoplasms; Endoplasmic Reticulum Stress; Enhancer of Zeste Homolog 2 Protein; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Mice, Inbred BALB C; Mice, Nude; Morpholines; Phenylurea Compounds; Proto-Oncogene Proteins; Pyridines; Pyridones; Reactive Oxygen Species; Transcription Factor CHOP; Tumor Suppressor Protein p53; Up-Regulation; Xenograft Model Antitumor Assays

Histone methylation is a context-dependent modification that regulates gene expression, and the trimethylation of histone H3 lysine 27 (H3K27me3) usually induces gene silencing. Overcoming colorectal cancer (CRC) chemoresistance is currently a huge challenge, but the relationship between H3K27me3 modification and chemoresistance remains largely unclear. Here, we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment. Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B (KDM6A/6B), thus decreasing the level of H3K27me3 in CRC cells. Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4 (a KDM6A/6B inhibitor) treatment significantly enhanced oxaliplatin-induced apoptosis. Conversely, when inhibiting the expression of H3K27me3 by EPZ-6438, an inhibitor of the histone methyltransferase EZH2, the proportion of apoptotic cells remarkably decreased. In addition, the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model. Importantly, we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression, which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site. Thus, the activated NOTCH signaling promoted the expression of stemness-related genes, which resulted in oxaliplatin resistance. Furthermore, oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment. Collectively, our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Benzazepines; Biphenyl Compounds; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; HCT116 Cells; Histone Demethylases; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Male; Methylation; Mice; Mice, Nude; Middle Aged; Morpholines; Oxaliplatin; Prognosis; Pyridones; Pyrimidines; Receptor, Notch2; Signal Transduction; Tumor Burden; Up-Regulation; Xenograft Model Antitumor Assays